Poly-adenosine diphosphate (ADP)-ribose (PAR) polymers are the product of post-translational modifications carried out by PAR polymerases (PARPs). PAR is polymerized by PARPs onto acceptor proteins using nicotinamide adenine dinucleotide (NAD+) as substrate (FIG. 1). PAR polymers are localized to distinct cellular structures in different phases of the cell cycle and localize to the mitotic spindle during mitosis (FIG. 2). There are at least 18 PARPs in the human genome: the domain structure for several PARPs is depicted in FIG. 3. However, the specific biological function and protein substrates of these PARPs are not fully characterized (Ame et al., Bioessays 26:882-893, 2004). The identification of the function and the substrates of each member of this family of proteins has been difficult to date.
PAR polymers are required for normal cell division and PARP knockouts in Drosophila melanogaster are embryonic lethal (Tulin et al., Genes Dev. 16:2108-2119, 2002). The concentration, length, and extent of PAR branching are regulated by a balance of activities of the PARPs and PAR glycohydrolase (PARG), a highly specific, processive endo- and exo-glycosidase (Hatakeyama et al., J. Biol. Chem. 261:14902-14911, 1986). Poly-ADP-ribose polymers have generally been implicated for a role in several different human diseases including cancer, ischemic injury, inflammatory diseases, cardiovascular diseases, and neurodegenerative disorders.
We have discovered that PARP13 and PARG modulate the activity of inhibitory RNAs (RNAi molecules) in the cell. Inhibitory RNA molecules may be used in the laboratory to knockdown the expression of a specific gene and its corresponding encoded protein in a cell. Inhibitory RNA technology is presently being used to develop molecular therapies for several diseases. Methods and compositions to increase the effectiveness of inhibitory RNA activity in vitro and in vivo (e.g., in a subject receiving molecular therapy) are presently desired.